The metabolism of cyclic nucleotides in mammalian sympathetic ganglia is easily altered by nerve stimulation, K ion and drugs. Nonetheless, their role in synaptic transmission in ganglia, as in brain, is not understood. Large increases in the ganglionic content of cGMP occur in ganglia treated with K ion or substances related to sodium azide. The response to K ion disappears in denervated ganglia, indicating that nerve terminal integrity is essential. By contrast, sodium azide causes an increase in cGMP in both intact and in denervated ganglia. In addition, K ion and sodium azide cause the release of cGMP from sympathetic ganglia. cGMP release produced by K ion depends upon Ca ions. cGMP release produced by sodium azide is depressed by Ca ions. These findings form the basis of a detailed study of guanylate cyclase, its chemistry and its role in ganglionic transmission. This information will be useful in the understanding of cGMP in nervous tissue.